The Interaction Between Alcohol Consumption and GSTM1 Genotype on Polycyclic Aromatic Hydrocarbon-DNA Adduct Levels in Breast Tissue1

Vol. 12, 911–914, September 2003 Cancer Epidemiology, Biomarkers & Prevention 911

Short Communication The Interaction between Alcohol Consumption and GSTM1 Genotype on Polycyclic Aromatic Hydrocarbon-DNA Adduct Levels in Breast Tissue1

Andrew Rundle, Deliang Tang, LaVerne Mooney, Introduction 2 Surah Grumet, and Frederica Perera We have been investigating the genetic and lifestyle determi- Departments of Epidemiology [A. R.] and Environmental Health Sciences nants of PAH3-DNA adduct levels in breast tissue and the [D. T., L. M., S. G., F. P.], Mailman School of Public Health, Columbia association between increased levels and breast cancer case- University, New York, New York 10032 control status (1–3). When adduct levels in tumor tissue from cases were compared with adduct levels in benign tissue from controls, high adduct levels were associated with breast cancer Abstract case-control status (1). The GSTM1-null genotype was associ- We investigated the association between alcohol ated with increased adduct levels in tumor and nontumor tissue consumption, GSTM1 genotype, and polycyclic aromatic from cases, but it was not associated with adduct levels in hydrocarbon (PAH)-DNA adduct levels in breast tissue. benign tissue from controls (2). Case-control differences in Women referred for breast surgery were enrolled prior adduct levels were stronger among those with the GSTM1-null to surgery, responded to an interview, and gave a blood genotype. sample. Women diagnosed with ductal carcinoma in situ As in many other studies of breast cancer (4, 5), we found and invasive ductal or lobular cancer were defined as current alcohol consumption to be associated with breast cancer cases, and women with benign conditions without atypia case-control status (3). The mechanisms through which alcohol were defined as controls. Paraffin-embedded tumor and may cause breast cancer are unknown, although several have nontumor tissue from cases and benign tissue from been have proposed (4). We have hypothesized that alcohol controls were retrieved from the pathology samples. consumption may influence breast cancer risk by inducing and GSTM1 genotype status was determined by PCR using suppressing genes responsible for the metabolism of xenobiot- WBC DNA, and PAH-DNA adduct levels were measured ics (6, 7). Several animal and cell culture studies have demon- in breast tissue using immunohistochemistry. In tumor strated that ethanol exposure alters PAH metabolism and in- and nontumor tissue from cases, the GSTM1-null creases adduct formation (7–11). Recent experiments with genotype was associated with increased adduct levels MCF-10F breast cells have shown that cotreatment of cells with among current alcohol consumers but not among B[a]P and ethanol produced higher adduct levels than treatment nondrinkers. In nontumor tissue, the interaction between with B[a]P alone (7). Ethanol treatment was shown to reduce -the expression of GSTP1, and the authors attributed the in ؍ genotype and alcohol consumption was significant (P 0.02), but in tumor tissue, the interaction did not achieve creased adduct levels to ethanol-induced reductions in B[a]P In benign tissue from metabolism by GSTP1 (7). GSTP1 and GSTM1 both detoxify .(0.10 ؍ statistical significance (P controls, there was no association between genotype and PAH, creating water-soluble conjugates that are less reactive adducts, regardless of drinking status. Among subjects than the PAH diol-epoxide metabolites (12, 13). Thus, the GST with the null genotype who drank alcohol, adduct levels enzymes are thought to prevent reactive xenobiotics from dam- were significantly higher in tumor and nontumor tissue aging DNA (2, 12). Here we extend our earlier findings on from cases than in benign tissue from controls. These GSTM1 and show that the GSTM1 genotype is a stronger results indicate the presence of a novel gene-lifestyle predictor of PAH-DNA adduct levels in subjects who were interaction that influences PAH-DNA adduct levels in regular alcohol drinkers. breast tissue from cases but not controls. This apparent difference in PAH metabolism in response to alcohol may Materials and Methods be an important clue as to how alcohol influences breast cancer risk. Study Population. Patient recruitment has been described previously in detail (1) and will only be described briefly here. From 1994 to 1998, women referred for breast surgery at Columbia-Presbyterian Medical Center were enrolled before surgery into a hospital-based case-control study. After informed Received 10/11/02; revised 5/5/03; accepted 5/22/03. consent had been obtained, during their preoperative tests, The costs of publication of this article were defrayed in part by the payment of patients took part in a structured interview covering established page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. reproductive breast cancer risk factors, active and passive 1 Supported by grants from the Department of the Army, United States Army smoking, dietary practices, other environmental and occupa- Medical Research and Materiel Command, DAMD17-94-J-4251, Noreen T. Hol- land Foundation, and National Cancer Institute Grant K07 CA92348. 2 To whom requests for reprints should be addressed, at Department of Environ- mental Health Sciences, Mailman School of Public Health, 60 Haven Avenue B1, New York, NY 10032. Phone: (212) 304-7280; Fax: (212) 544-1943; E-mail: 3 The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; B[a]P, [email protected]. benzo(a)pyrene; GST, glutathione S-transferase; BBD, benign breast disease.

Table 1 Adduct levels in breast tissue by current drinking status and GSTM1 genotype

Current drinker Current non-drinker GSTM1 ϩ/ϩ, ϩ/Ϫ GSTM1 null GSTM1 ϩ/ϩ, ϩ/Ϫ GSTM1 null Tumor tissue 0.32 (1.72) n ϭ 25 0.59 (2.09) n ϭ 21a 0.35 (1.81) n ϭ 17 0.41 (1.67) n ϭ 19 Nontumor tissue 0.30 (1.55) n ϭ 25 0.51 (1.87) n ϭ 20b 0.38 (1.66) n ϭ 14 0.34 (1.64) n ϭ 17 Benign tissue 0.30 (1.45) n ϭ 9 0.34 (1.59) n ϭ 28c,d 0.34 (1.63) n ϭ 29 0.43 (1.55) n ϭ 15 a P ϭ 0.002 comparing adduct levels in tumor tissue by GSTM1 status. b P ϭ 0.003 comparing adduct levels in nontumor tissue by GSTM1 status. c In current drinkers who are GSTM1 null, adduct levels in tumor tissue are significantly higher than in benign tissue (P ϭ 0.002). d In current drinkers who are GSTM1 null, adduct levels in nontumor tissue are significantly higher than in benign tissue (P ϭ 0.01).

tional exposures, and vitamin consumption. Patients whose analysis with the Cell Analysis System 200 microscope confirmed diagnosis was of ductal carcinoma in situ or invasive (Becton-Dickinson, San Jose, CA) running the Cell Measure- ductal or invasive lobular cancer were defined as cases. Patients ment software. A total of 50 cells (5 fields with 10 cells/field with rare tumors were not included because the small numbers scored) were measured on each tissue slide. Results are re- precluded analyses by histological type. Patients diagnosed ported in optical density units as described previously (15). with BBD or BBD with hyperplasia were classified as controls. Serial tissue slices from laboratory control breast tissue speci- Because patients were enrolled before diagnosis, matching of mens previously shown to have low and high staining for BBD controls to cases was not possible. BBD patients whose adducts were used as negative and positive control samples, diagnoses were other than these categories (e.g., BBD with respectively, and were run with every batch. As an additional atypia or lobular carcinoma in situ) were excluded from anal- negative control, in each batch, a laboratory control sample was ysis because of their elevated risk of future breast cancer. Breast run without the primary antibody. cancer patients seen at Columbia-Presbyterian Medical Center Statistical Methods. Absorbance data reflecting the extent of for follow-up surgery (e.g., mastectomy or re-excisions) after staining for PAH-DNA adducts was log (ln) transformed for an initial surgical biopsy at another hospital were excluded analyses to produce a more normal distribution. Results are from the study. Additional exclusion criteria included a prior reported as geometric means and geometric SDs (16). As part history of cancer at any site except basal skin cancer, current of the interview, subjects were asked to estimate the average pregnancy, recent bone fractures, or recent breastfeeding. The number of drinks they consumed per week during the 12 last two exclusion criteria were included because these factors months before the interview. Study subjects who responded that were thought to interfere with biomarkers used in other aspects they drank 0 drinks/week were classified as nonconsumers, and of this study. Study subjects responded to an interviewer- subjects who responded that on average they drank more than administered questionnaire and provided blood samples. Sam- 0 drinks/week were classified as regular current consumers of ples of paraffin-embedded tumor and nontumor tissue were alcohol. Subjects were cross-classified into four groups based retrieved from pathology blocks from cases, as were samples of on their GSTM1 genotype status and whether they were current benign tissue from BBD controls. Thus, two tissue samples, alcohol consumers. For each tissue type (tumor, nontumor, and tumor and nontumor, were available from cases, and one tissue benign), geometric mean adduct levels were calculated for each sample, benign, was available from the BBD controls. of the four alcohol consumption/genotype strata. t tests were A total of 119 cases and 108 BBD controls were enrolled used to determine whether GSTM1 status was associated with with a response rate of 76%. Data on adduct levels, GSTM1 adduct levels within each stratum of alcohol consumption. status, and alcohol consumption were available from 82 cases Within each tissue type, linear regression analyses, with inter- for analyses in tumor tissue, 76 cases for analyses in nontumor action terms for the joint effects of genotype and alcohol tissue, and 81 controls for analyses in benign tissue. consumption, were used to determine whether the association Laboratory Methods. To assess individual GSTM1 genotype, between GSTM1 and adduct levels differed by alcohol con- DNA was extracted from blood leukocytes and analyzed by sumption status. t tests were used to determine whether, among PCR as described previously (14). The primers used in the PCR subjects who were GSTM1 null and drank alcohol, adduct mix were G5 (5Ј-GAA-CTC-CCT-GAA-AAG-CTA-AAG-C) levels were higher in cases versus controls. and G6 [5Ј-GTT-GGG-CTC-AAA-TAT-ACG-GTG-G (14)]. As a control to detect PCR failures, the assay included primers for the ␤-globin gene. Women who were homozygous (ϩ/ϩ)or Results heterozygous (Ϫ/ϩ) for GSTM1 were classified as GSTM1 Among current alcohol consumers, the GSTM1-null genotype positive, and those who were homozygous deleted (Ϫ/Ϫ) were was significantly associated with higher adduct levels in tumor classified as GSTM1 null. and nontumor tissue, but not in benign tissue from controls (see The immunohistochemical assay for PAH-DNA adducts Table 1). Among nondrinkers, GSTM1 genotype was not asso- and its performance characteristics have been described exten- ciated with adduct levels in any of the tissues (see Table 1). In sively elsewhere (1, 3, 15). Briefly, using standard immuno- tumor tissue, the apparent interaction between GSTM1 status histochemical techniques, tissue slides were incubated with and current alcohol consumption on adduct levels approached anti-benzo(a)pyrene-diol epoxide-DNA monoclonal antibody but did not reach statistical significance (P ϭ 0.10). However, 5D11, kindly provided by Dr. Regina Santella. Staining was in nontumor tissue from cases, the interaction term was signif- accomplished using a biotinylated antimouse secondary anti- icant (P ϭ 0.02), indicating that the association between body (Vector Laboratories, Burlingame, CA), ABC reagents, GSTM1 and adduct levels significantly differs by alcohol con- and diaminobenzidine. Methyl green was used as a counter- sumption status. Within the GSTM1-null/alcohol consumer stain. Nuclear staining was quantified using absorbance image stratum, adducts levels were significantly higher in tumor tissue

from cases than in benign tissue from controls and significantly ence adduct levels in a substrate-specific manner (22). How- higher in nontumor tissue from cases compared with benign ever, given the evidence that alcohol consumption inhibits tissue from controls (see Table 1). GSTP1 expression, genotype analyses may not be useful in understanding the role of GSTP1 in adduct formation. Subjects were defined as current consumers if they re- Discussion ported any consumption on a regular weekly basis over the past We report here on a gene-lifestyle interaction that influences year. Among the consumers, the average number of drinks/ PAH-DNA adduct levels in breast tissue from cases but not in week was 4.82, with a range of 0.07–36 drink(s)/week. The tissue from BBD controls. This is an extension of our prior interview question on current alcohol consumption asked about work showing that GSTM1 was associated with PAH-DNA drinking patterns in the past year; however, many of the women adduct levels in breast tissue from cases but not from BBD who consumed alcohol reported that they had been drinking controls (2). The presence of the interaction in cases only more since they had been told they needed breast surgery. Thus provides further evidence that women with breast cancer differ because our question on past year consumption may underes- from women with benign conditions in some as yet unknown timate very recent consumption patterns, we did not categorize manner that makes GSTM1 a more important determinant of the women who reported the lowest alcohol consumption, for PAH-DNA adduct levels in breast tissue (2). Additionally, instance 0.07 drink/week, as nondrinkers. Because the inter- case-control differences in adduct levels were strongest among view was conducted before surgical biopsy, and none of the women who consumed alcohol and were GSTM1 null. women knew whether they were cancer free, we do not expect The analyses presented here were motivated by the recent changes in recent drinking patterns to be differential by case- report of breast cell culture experiments showing that ethanol BBD control status. Overall, the data suggest that these women increases the extent of adduct formation in cells treated with were relatively light consumers of alcohol, and the effect ap- B[a]P (7). The authors attributed the increased levels of adducts pears to occur at low levels of alcohol consumption. This is to ethanol-induced reductions in the expression of GSTP1 that consistent with the work of Barnes et al. (7), who treated they observed in the cell cultures (7). GSTP1 and GSTM1 both MCF-10F cells with alcohol at concentrations consistent with metabolize PAH, creating water-soluble conjugates that are less blood alcohol levels achieved by drinking 1–3 drinks. The level reactive than the PAH diol-epoxide metabolites; however, nei- of drinking seen in our study is consistent with the popularly ther gene is involved in the metabolism of ethanol (12, 13). This held but unproven belief that a glass of red wine a day is overlapping specificity may provide multiple layers of defense protective against heart disease (23–25). Should these findings against genetic insult from PAH. Our data indicate that the be replicated and prove to be causal, current recommendations GSTM1 genotype is an important predictor of PAH-DNA ad- regarding alcohol consumption may need to be reconsidered duct levels in subjects who were regular alcohol consumers but (23–25). not among nonconsumers, suggesting that other detoxifying In noting the apparent case-control differences in the re- pathways were compromised among alcohol consumers. sponse to alcohol consumption, we hypothesize that there exists One limitation of our research is that data are not available some constitutive difference between cases and controls in gene on GSTM1 and GSTP1 expression in the tissue sections. The expression in response to alcohol. It is possible, however, that literature on whether alcohol alters GST expression is incon- this differential response represents a local effect of alcohol on sistent (7, 8, 17–21). There appear to be organ- and species- tumor tissue. It is possible that, in some manner, alcohol alters specific differences in whether alcohol exposure inhibits or metabolism in tumor cells such that GSTM1 is an important induces GST expression, and the effects appear to differ by GST determinant of adduct levels in tumor tissue, but metabolism in subclass. A recent study in rats found that long-term ethanol normal breast cells is unaffected. The observed interaction treatment induced GST-␮ and GST-␣ but not GST-␲ class between GSTM1 and alcohol consumption in nontumor tissue activity in liver cells, yet a study in hamsters observed no from cases argues against the hypothesis that the effect is a increase in GST-mediated metabolism of B[a]P in response to result of alcohol influencing metabolism in tumor tissue only. ethanol treatment (8, 17). A recent study using cDNA expres- However, because the nontumor tissue analyzed in this work sion arrays found that chronic ethanol feeding was associated was adjacent to the tumors in situ, the possibility of a field with increased GSTM1 expression in C57BL/6J, ethanol- effect or that the tumor influenced metabolism in nearby tissues preferring mice but not in BALB/c, ethanol-avoiding mice (21). cannot be ruled out. Further work is needed to determine Our results suggest that alcohol consumption does influence whether the apparent differential responses to alcohol represent PAH metabolism and that GSTM1 is not inhibited by alcohol a constitutive difference between cases and controls or a local consumption. In addition to the possibility that alcohol influ- effect of alcohol on metabolism in and around the tumor. ences GSTP1 expression, alcohol may alter the expression of Another consideration in assessing the apparent case- important phase 1 genes, such as CYP1B1, which activates control differences in adduct levels is the use of women with PAH to the reactive diol-epoxide form (7). Increased availabil- BBD as the control group. Although the BBD control group ity of reactive metabolites would also be hypothesized to make only included diagnoses with a low risk for future breast cancer, GSTM1 genotype a more important determinant of adduct lev- a concern is that the BBD controls may overly share risk els among alcohol consumers. factors, both measured and unmeasured, with the cases (26). To If alcohol consumption is indeed reducing the expression the extent that an exposure of interest is positively associated of GSTP1 in our subjects, and this accounts for the interaction with another risk factor overrepresented in the controls, the use between alcohol consumption and GSTM1, the presence of the of BBD controls will cause risk estimates for the exposure to be interaction in cases but not controls suggests that the effect of attenuated to the null. However, in comparisons of odds ratios alcohol on GSTP1 expression is stronger in cases than BBD for known breast cancer risk factors calculated using a healthy controls. Differences in responsiveness to alcohol in terms of control group and the BBD control group, we did not find that gene inhibition or induction may, especially for genes related to the use of BBD controls resulted in a consistent trend of PAH metabolism, represent an important determinant of breast attenuated risk estimates (3). cancer risk. GSTP1 has a polymorphism that appears to influ- In conclusion, we report here on a novel gene-lifestyle

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Andrew Rundle, Deliang Tang, LaVerne Mooney, et al.

Cancer Epidemiol Biomarkers Prev 2003;12:911-914.

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